A French nationwide study compared various conditions and healthcare use of individuals < 65 years with a Down’s syndrome to those without

Few regular national clinical data are available for individuals with Down’s syndrome (IDS) bearing in mind that they are subject to countries variations in medical termination of pregnancy and screening. Individuals < 65 in 2019 were selected in view of the low number of older IDS. Thus, 98% of 52.4 million people with correct data were included from the national health data system. IDS (35,342) were identified on the basis of the International Classification of Diseases 10th revision code (Q90). Risk ratios (RR) were calculated to compare the frequencies in 2019 between IDS and individual without Down’s syndrome (IWDS) of use of health care. The prevalence of IDS was 0.07% (48% women), comorbidities were more frequent, especially in younger patients (24% < 1 year had another comorbidity, RR = 20), as was the percentage of deaths (4.6%, RR = 10). Overall, tumours were less frequent in IDS compared with IWDS (1.2%, RR = 0.7) except for certain leukaemias and testicular tumours (0.3%, RR = 4). Cardiac malformations (5.2%, RR = 52), dementia (1.2%, RR = 29), mental retardation (5%, RR = 21) and epilepsy (4%, RR = 9) were also more frequent in IDS. The most frequent hospital diagnoses for IDS were: aspiration pneumonia (0.7%, RR = 89), respiratory failure (0.4%, RR = 17), sleep apnoea (1.1%, RR = 8), cryptorchidism (0.3%, RR = 5.9), protein-energy malnutrition (0.1%, RR = 7), type 1 diabetes (0.2%, RR = 2.8) and hypothyroidism (0.1%, RR = 72). IDS were more likely to use emergency services (9%, RR = 2.4), short hospital stay (24%, RR = 1.6) or hospitalisation at home (0.6%, RR = 6). They consulted certain specialists two to three times more frequently than IWDS, for example cardiologists (17%, RR = 2.6). This study is the first detailed national study comparing IDS and non-IDS by age group. These results could help to optimize prenatal healthcare, medical and social support.


Evolution of French data on children and mothers characteristics and DS screening
The number of children born in France was around 800,000 per year at the end of the 1970s, falling to 741,000 in 1994.There was then a steady increase to a peak of 830,000 in 2012, followed by another rapid fall (753,000 in 2019 and 720,000 in 2022) (INSEE, National Institute for Statistics and Economic Studies) 26 .In 2022, women gave birth to their first child at a mean age of 31.0 years, four and a half years later than in 1974.In 2019, 42,800 babies were born to mothers aged 40 or over (5.7% of births were so-called "late births"), 25% of newborns were the first children of mothers aged 35-44 years and 36% were the first children of mothers aged 45-50.For every 100 women born in France, eight children were born to mothers between the ages of 40 and 50 years, whereas the corresponding figure was 19 children for women born elsewhere.Women in managerial or higher intellectual occupations had the highest rates of late deliveries among women who had already worked: 11 children per 100 women between the ages of 40 and 50 years.
It has been possible to perform cytogenetic analysis on cultured amniocytes since the 1970s.This has made prenatal diagnosis feasible in pregnant women aged 38 years and over and this procedure is reimbursed in France.The first recommendations for population-based screening concerned the use of serum markers in the second trimester of pregnancy 27 .The possibility of earlier prenatal diagnosis based on chorionic villus sampling in the 1980s met the need for screening in the first trimester.

Data source
The SNDS collects individual information from the various insurance schemes, the types of healthcare used and the amounts reimbursed 25 .It does not record diagnoses made in non-hospital settings or the results of clinical examinations and investigations.However, it does include information about long-term disease (LTD) status for a specific condition, which justifies 100% reimbursement of specific healthcare expenditures for at least five years, if requested by the patient's general practitioner (GP).The list of LTDs is published by decree.A pseudonymized identification number is used to link above information with data from the national hospital discharge database concerning stays in public and private hospitals: short-stay hospitalization (SSH), hospitalization at home, or hospitalization in psychiatric hospitals and rehabilitation facilities.LTD and hospital diagnosis are coded using the International Classification of Diseases 10th revision (ICD -10).Deaths are also collected in the SNDS.
For comorbidities, we also used data from "Healthcare Expenditures and Conditions Mapping", a tool based on the SNDS developed for the analysis and monitoring of disease burden through evaluations of healthcare use 28 .This tool can be used to identify 58 diseases or chapter of diseases through the use of medical algorithms based on the reasons for hospitalization, long-term disease diagnoses and the reimbursement of specific treatments for certain diseases, for a given year and a period up to four years preceding that year.For tumors, exclusive algorithms identified different states of the same disease related to active treatment or acute care or to long-term follow-up and chronicity or under surveillance.

Study population
This large cross-sectional observational study focused on individuals with national health insurance coverage receiving at least one healthcare reimbursement in 2019 (98.5% of the population residing in France: 67.25 million on January 1, 2019 according to the INSEE and 52.3 million aged < 65 years) 26 for estimations of overall

Variables analysed
It involved: age class (as of January 1, 2020), sex, residence in a French overseas territory (FOT, including the French West Indies, French Guiana, and Réunion Island), date of death, comorbid conditions (categories and frequent specific detailed diseases from Healthcare Expenditures and Conditions Mapping, together with any LTDs with a frequency ≥ 0.1% for the DS group), diagnoses during hospital stays (by chapter, and detailed diagnoses with a frequency ≥ 0.1% associated with at least one hospital stay for the DS group, to identify admissions for acute disease or requiring a hospital procedure, for acute and chronic conditions) and hospital care and medical visits.
C2S (Complémentaire santé solidaire), a solidarity-based supplementary health insurance, is a renewable benefit granted for one year to people with a limited resources and a stable and regular residence in France.The household covered by C2S includes the applicant, the applicants spouse or partner and any children.In 2020, the annual income limit in mainland France for C2S eligibility was between €9,032 and €12,193 for a single person.This limit is below the poverty threshold, defined as 60% of the median income, which was €13,224 in France in 2019.

Analyses
The prevalence of DS was estimated in 2019, globally and for the population of individuals under the age of 65 years.For this second population, we compared individual characteristics, healthcare use and comorbid conditions between IDS and NIDS, on the basis of rate ratios (RR).Finally, we considered the principal diagnosis during hospitalization for individuals with at least one SSH.
We also compared primary healthcare consultation and hospital use in 2019.The median number and interquartile range (IQR) were calculated for the number of medical visits, for individuals with at least one such visit, to assess differences in the intensity of healthcare use between IDS and IWDS.We also analyzed the male and female populations separately, to check for sex-specific conditions.Given the almost exhaustive nature of the population and the large sample size, we report crude RR without 95% confidence intervals and p-values 29 .
SAS software (version 7.13, SAS Institute Inc, Cary, NC, USA) was used for statistical analysis.

Ethical approval
A specific ethics committee approval was not required for this study.The French national health insurance (CNAM) in charge of the SNDS (système national des données de santé) has permanent access to the pseudonymized reimbursement data in application of the provisions of articles

Population characteristics
In 2019, the prevalence of DS was 0.055% in individuals of all ages (Fig. 1) and 0.068% when IDS over the age of 65 years were excluded (3% of the 36,464 IDS).For IDS under the age of 10 years (born in 2009-2019) the prevalence was relatively uniform, at about 0.07%.IDS prevalence decreased to 0.05% for those aged 10-19 years (born in 2000-2009) and increased to 0.08% for those aged up to 30 years (born in 1990-1999).Prevalence then stabilized at about 0.07% until the age of 54 years, after which it decreased rapidly.Women accounted for 48% of cases of DS (Table 1).A quarter of IDS had at least one other LTD (RR = 2.3).This proportion was uniform over the different age groups, but RR values decreased with age, due to an increase in the frequency of other LTDs with age in IWDS (1 year, RR = 20.1;50-64 years, RR = 1.3).The proportion of IDS was higher in FOT, particularly for the youngest age group (< 1 year 0.15%, RR = 2.3; 50-64 years 0.05%, RR = 0.8).
Social precariousness, defined in relation to a threshold for low income (that used for C2S eligibility), was more frequent for IDS over all age ranges (24.6%, RR = 1.7), but particularly for the youngest, whose income was entirely dependent on their family or household (< 1 year, 43%, RR = 2.2).
Overall mortality was higher in IDS under the age of 65 years (4.6%, RR = 10.2) (Table 1).Mortality for IDS under the age of one year was particularly high and considerable excess was noted (4.3%, RR = 18.9) and also for those aged 1-4 years (0.9%, RR = 22.5), or 5-9 years (0.3% RR = 16.8).Mortality subsequently reached a relatively stable plateau, with an RR of between 6 and 12. Mortality then began to increase again in the DS population after the age of 30-39 years, to reach 16.9% between the ages of 50 and 64 years.
For infectious diseases, IWDS, particularly adults, were more likely to have LTD status for chronic viral hepatitis B without a delta agent (0.3%, RR = 5.3) (Table 4).IDS were also more likely to be hospitalized for intestinal viral infections and other types gastroenteritis and colitis (0.4%, RR = 4.4) particularly during childhood (Table 3).
IDS were more likely to have ophthalmological diseases (Table 3), such as LTD status for keratoconus, although the frequency of such diseases remained low (0.1%, RR = 26.4).IDS were also more frequently hospitalized for eye diseases (1.3%, RR = 4.6) and ENT conditions (1.2%, RR = 7), such as otitis media, cholesteatoma of the middle ear and conductive deafness.www.nature.com/scientificreports/Cardiovascular diseases were also present in excess among IDS (9.5%, RR = 3.7) (Table 2).An analyses of LTDs showed that there was a very high frequency of cardiac malformations in IWDS (5.2%, RR = 52.2),particularly those under the age of four years (around 15%) (Table 3).Valvular disease (0.9%, RR = 5.8) and heart failure (1.2%, RR = 6.7) were more frequently reported in IWDS, as were rhythm and conduction disorders, albeit to a lesser extent (1.3%, RR = 2.3) (Table 2).The RRs for these conditions were higher in younger patients.Hospitalization for pulmonary hypertension was also more frequent among IDS than among those without DS (0.1%, RR = 21.9),particularly for younger age groups.

Healthcare use
In 2019, IDS were more likely than IWDS to have at least one visit to any type of healthcare (Table 5).For general practitioners (GP), the frequency of visits was similar between the two groups (88.1%,RR = 1).However, the median number of annual consultations was higher for IDS (5 vs. 3).They also visit more frequently medical specialists and more particularly ENT specialists (22.1%,RR = 3.0), cardiologists (17.2%, RR = 2.6), and neurologists (5.1%, RR = 2.4).They also had a higher frequency of visits for some surgical specialties, such as pediatric (2.1%, RR = 3.1) and thoracic (0.3%, RR = 1.9) surgery.IDS also consulted physiotherapists (17.6%, RR = 1.2) and nurses (45%, 1.7) more frequently than IWDS, particularly for the younger age groups, but they did not consult dentists more frequently (38%, RR = 0.9).The median number of annual visits to healthcare professionals as outpatients was generally similar between the two groups, except for physiotherapists (24 vs. 12) and psychiatrists (4 vs. 3), who were more frequently consulted by IDS.
For some of the most frequently used medical specialties, the frequency of visits was high for the youngest age groups, subsequently decreasing or stabilizing with age (Fig. 2).This pattern was observed for pediatricians, but also for ENT specialists, ophthalmologists, cardiologists and physiotherapists.For other specialists, such as neurologists, gynecologists and dermatologists, the frequency of visits increased with age or stabilized at a uniform level.

Discussion
This first large nationwide observational study comparing individuals under the age of 65 years with and without DS identified on the basis of hospital diagnoses and LTD status.Individuals with DS more were found to be more likely to live in deprived areas, and to have excess mortality and various comorbidities, particularly for the youngest age groups.They were also more likely to have had at least one stay in a hospital of some type during the course of the year, with various diagnoses, and to have attended outpatient visits with various specialists other than dentists and gynecologists.
The number of IDS of all ages in France was 36,500 in 2019 (0.07%).A study of European countries (2011-2015), based on birth registry data and modeming techniques, including advances in surgery, yielded very similar estimates for the number (35,684) and prevalence (0.07%) of livebirths of IDS in 2015 for France 8 .Global estimates (1900-2015) including elective terminations reported a steady increase in the prevalence of DS after the 80s, with a stead decrease in prevalence once elective terminations were excluded from the calculation, except in the US, which displayed a slight increase even after the exclusion of elective terminations 8 .
The methods used to screen for DS in France were recommended by French National Authority for Health and the regulated by legal decrees published and updated successively in 1997, 2009, and 2018).Physicians inform all pregnant women that nuchal translucency can be measured at the first ultrasound examination, between 11 and 13 weeks ± 6 days, and both physicians and midwives propose blood tests for DS.Organized screening was introduced in the middle of the 1990s.The results obtained, including those for maternal serum markers, were used to calculate the risk of DS during the first or second trimester of pregnancy.Women for whom this screening revealed a high risk of DS were offered a diagnostic examination-amniocentesis or chorionic villus sampling-to determine fetal karyotype.At the end of 2017, the HAS introduced first-trimester screening of maternal blood for free fetal DNA into its strategy for detecting DS in the fetuses of women at high risk.
We observed no decrease in the prevalence of livebirths affected by DS after the 1980s in this study.Instead, there was a slight increase from the early 1990s to 2000, with the implementation of organized screening beginning in France in the middle of the 1990s 27 .Surprisingly, the introduction of screening was followed by a slight increase in prevalence, followed by a stabilization among children aged 0-4 years in 2019.Many possible explanations have been proposed for the variations observed (sociodemographic factors, abortion policies or funded screening and increases in survival, not considered here).Testing for free fetal DNA in maternal blood was officially recommended in 2018 but was introduced the year before, leading to the plateau in prevalence (0.07%) observed for children under the age of four years 27 .
IDS were more likely to be covered by universal health insurance, suggesting a low household income.This pattern was particularly marked for the youngest (< 1 year and 1-4 years old) IDS and their households.Similarly, poor social conditions were found to be more frequent in IDS over the age of 18 years in Denmark 30 .These results may reflect poor access to prenatal healthcare use, a poor understanding of the nature and goals of screening or poor access to specific elective termination procedures subject to specific limitations or requiring a clear understanding and informed consent.These hypotheses are supported by results from an English study (1998-2007)  reporting lower rates of antenatal DS detection and elective abortions for DS in more deprived areas 31 .
Moreover, data from representative perinatal surveys performed on the French mainland in 2010 and 2016, indicate that 10% of the women surveyed underwent no DS testing.Testing was not offered to 12% of these women, and 49% refused testing 32 .Women born outside France were less likely to undergo blood tests, because www.nature.com/scientificreports/they more frequently refused such testing, even if their antenatal care was adequate.Livebirths affected by DS are more frequent in FOT, where deprivation is more frequent 33 than on the mainland, particularly for the youngest age groups.FOT also have specific cultural characteristics, higher rates of migration and refusal of testing, even in situations in which perinatal care is adequate, and there are differences between FOT.It was also reported that, in 2016, for all children under the age of 18 years in mainland France, those in deprived areas, regardless of their DS status and based on the same markers, were more likely to have LTDs, poorer access to specialists and larger numbers of emergency department visits and hospital admissions 34 .Most of the diseases more frequent among IDS identified here have already been described as more frequent in this population in disease-specific studies, based on frequencies or reviews, but rarely in a single study, by age, with www.nature.com/scientificreports/ a large panel of diseases.Care consumption is also little described.Some of these diseases, such as congenital heart disease in children, have also been implicated in the excess mortality reported for young IDS.Despite improvements in care, excess mortality persists among IDS and is still associated with the severity of various congenital heart defects and extracardiac malformations or complications following treatment for congenital heart diseases, such as pneumonia and respiratory infection or failure 11,[35][36][37] .Nevertheless, in our analysis of LTDs revealed a relatively high frequency of cardiac malformations, particularly in those under four years of age (around 15%), requiring surgical treatment.Coronary artery disease also occurred in adults with DS, but at rates similar to those in the general population, and at a similar age; similar results were obtained for stroke 15 .Hospitalization for pulmonary hypertension was also more frequent among IDS, and at younger ages.Surveillance of this condition during childhood is important, because it is often associated with cardiovascular diseases; valvular disease, heart failure, rhythm problems and conduction disorders also reported, but to a lesser extent 37 .Chronic respiratory diseases were more frequent in IDS, who were also more likely to have asthma and chronic respiratory insufficiency.Pneumonitis was the respiratory condition most frequently diagnosed in IDS at the hospital, due particularly to the aspiration of food and other substances, as a result of the dysphagia and swallowing disorders frequently occurring in this population 38 .Young people with DS were also more frequently hospitalized for iron deficiency anemia, and for protein-energy malnutrition before the age of four years.They also more frequently had LTD status for certain rare diseases and hospitalizations for paralytic ileus and intestinal occlusions without hernia.
In a study in the USA between 2013 and 17, heart disease, Alzheimer's disease and other forms of dementia, and cancer were more common causes of death in the youngest adults with DS than in the general population of same age 14 .A similar pattern was observed here.Pneumonia, pneumonitis, and respiratory failure were more frequent in IDS of all ages, with ethnic differences in the cause of death reported for adults with DS in the American study.The risk of death was higher in IDS for most of diseases, but was lower for heart disease in adults, and death rates from cerebrovascular disease were similar to IWDS 5 .Cancers were less frequently recorded as a cause of death in IDS, but this is unsurprising given that IDS tend to die at younger ages.The exception to the rule was some types of leukemia and testicular cancers that occur in young adults.A higher frequency of hospital admissions, for testicular abnormalities or cryptorchidism, was recognized as a risk factor.
We report here that IDS, particularly the youngest, were more frequently admitted to hospital, particularly those with cardiac diseases 21,23 .The frequency of diagnoses differed between the ISD and NSD.Those with DS were more frequently hospitalized at home before the age of 10 years and when nearing the end of life than NIDS.IDS visited specialists and surgeons more frequently, in relation to the conditions more frequent in this population, particularly at young ages.They also visited physiotherapists more frequently.

Strengths and limitations
This cross-sectional observational study concerned 52.3 million individuals under the age of 65 years covered by the national health insurance system and receiving at least one reimbursement for healthcare in 2019 (98.5% of population).The number of IDS is very similar to that in a study in which the size of this population was estimated, because, as reported here, IDS had high rates of healthcare use, hospital diagnoses and potentially life-threatening or disabling LTDs requiring regular, costly, long-term care.
C2S is allocated for at least one year, with an entitlement to 100% reimbursement for all healthcare expenditure, regardless of the health status of the individuals covered, according to a fixed threshold for household or individual income.It can be renewed annually, subject to the claimant making an application.

Conclusion
This study is one of the largest and most recent to investigate the prevalence of comorbid conditions in individuals with DS, and is therefore ideal for analyses of certain relatively rare conditions.Our results were obtained in a context in which there neither screening nor access to elective abortion for DS is limited and in which universal healthcare cover is available.They suggest that there is a high frequency of comorbid conditions among IDS born alive.The use of specialist healthcare by these individuals is consistent with improvements in their lifespan and healthcare for the various conditions they present.Nevertheless, excess mortality persists, especially among the youngest.Mothers from deprived areas were more likely to have children with DS, raising questions about recommendations for early screening and the care of IDS, which may be inadequate in deprived areas.These data suggest that improvements are required in comprehensive counselling, prenatal healthcare and, after birth, in social support for all IDS and their families.

Figure 1 .
Figure 1.Prevalence of Down's syndrome in France in 2019 by sex, age and year of birth (N = 36,464).

ContinuedTable 3 .
Comparison of hospital diagnoses (ICD-10 code)* frequencies for individuals with at least one hospitalization in 2019 by age between individuals with and without DS (rate ratio).*Diagnosis with a frequency ≥ 0.1% were reported.

Table 1 .
Comparison of sociodemographic characteristics, LTD and death frequencies by age between individuals with and without DS (rate ratio).DS Down's syndrome, RR rate ratio, LTD long-term disease, FOT French overseas territories, C2S solidarity-based supplementary health insurance (low income).

Table 2 .
Comparison of diseases managed, using mapping tools*, by age between individuals with and without DS (rate ratio).*conditions with a frequency ≥ 0.1% are reported.

Table 4 .
Prevalence of LTDs (ICD-10 code)* for individuals with at least one LTD in 2019 by age between individuals with and without DS (rate ratio).*Diagnosis with a frequency ≥ 0.1% were reported.

Table 5 .
Frequency of individuals with DS with at least one outpatient or inpatient visit, emergency department visit or hospital stay in 2019 relative to individuals without DS, by age, and the median number of visits and hospital admissions.*Children could be counted in both categories if they had more than one stay or visit.